Discussion
Our case report illustrates a new type of cloxacillin-induced liver injury, acute vanishing bile duct syndrome. Strengths of this study include the collaboration between the clinicians and pathologists in managing this patient by having liver biopsy to determine the specific pattern of her cholestasis and liver failure, as opposed to undifferentiated DILI. The patient was also followed closely as an outpatient by her medical providers, including LT team, which provided information about the persistence of her disease after discharge. One limitation of this study is the fact that the patient reported a penicillin allergy, which may have made her more susceptible to a cloxacillin reaction than non-allergic patients, though reported penicillin allergies are often unreliable27. The other limitation is that patient unfortunately had a fall and developed multiple traumatic fractures, which likely contributed and accelerated deterioration of her liver disease and her passing away before getting the LT.
Using Google Scholar, we found four additional cases of cloxacillin-induced livery injury requiring a liver biopsy. One retrospective study examined a series of drug rechallenge cases, from the Global Safety Database, where patients who had possible DILI were given the same drug while monitoring liver enzymes27. One of the 88 confirmed positive rechallenge cases was caused by cloxacillin-related injury, and liver biopsy showed a portal lymphocytic infiltrate with some eosinophils28. A similar retrospective study examined 77 possible or probable DILI cases secondary to penicillinase-resistant penicillins reported to the Swedish Adverse Drug Reactions Advisory Committee29. One case related to cloxacillin underwent liver biopsy which showed cholestasis with moderate inflammation including some eosinophilic infiltrate29. No specific demographic or clinical information was reported for either of those two cases.
There have been only two case reports of cloxacillin-induced liver injury that included both clinical and histopathologic information25-26. Both patients were female, aged 69 and 77 years, and presented with jaundice and pruritis. Additionally, the first patient had hepatomegaly and the second had weakness and maculopapular rash. They both had a cholestatic liver injury pattern, but their ALP (1126 and 394), AST (18 and 313) and total bilirubin (255 and 221) levels were lower than those seen in our case. Eosinophilia was only noted in the second patient. Both liver biopsies showed moderate to severe intrahepatic cholestasis, which was canalicular in the first case and hepatocellular in the second. Both also had up to moderate portal inflammation, and mild lobular necroinflammation. Additionally, the first case showed occasional hepatocyte variation and multinucleation, Kupffer cell hyperplasia with lipofuscin and ceroid pigmentation, and minimal steatosis. Normal bile ducts were seen in the first case and no abnormalities were documented in the second. Prednisone was only used for the second patient, but both had normal liver enzymes and recovered clinically within 60 and 10 days, respectively.
Altogether, lobular or portal inflammation was described in all four reported cases of cloxacillin-induced liver injury, whereas eosinophils were documented in three cases. Three patients had cholestasis with moderate to severe or prominent cholestasis in canalicular or hepatocellular patterns in two cases. Bile ducts were reported as normal in one case and assumed to be normal in the other three. Both cases that were followed clinically had a full recovery.
The prognosis of drug-induced VBDS has been variable in general. In a case series of 8 patients with drug-induced VBDS followed with sequential liver biopsies, three recovered clinically, three recovered biochemically and clinically, and one developed biliary cirrhosis30. In a 10-year retrospective study, from 2004 to 2014, by the US DILI network, 26 of 363 (7%) patients that underwent a liver biopsy had bile duct loss (14 lost >50% bile ducts, while 12 lost 25-50% bile ducts)31. Compared to patients without bile duct loss, patients with bile duct loss had a higher risk of developing chronic liver disease, persistent cholestasis after six months (94% vs 47%), and death within two years of follow up (27% vs 9%).
Treatment for drug-induced VBDS is largely similar to that for other types of drug-induced cholestasis, including immediate withdrawal of the culprit drug and preventing re-exposure, as well as ursodexycholic acid to protect against toxic bile salts15,32-33. Steroids and other immunosuppressants may be used when there is an indication of allergic reaction such as eosinophilia, lymphadenopathy, rash or syndromes like Stevens-Johnson syndrome33. Plasmapheresis has been used successfully in a case of loxprofen-induced ductopenia in an adolescent female unresponsive to initial treatment measures14. In cases that progress to biliary cirrhosis, supportive management and LT would be indicated18.
Our case shows that cloxacillin-induced cholestasis can be secondary to acute ductopenia, which is associated with more severe clinical presentations and worse outcome than the previously described bland cholestasis. Liver biopsy is therefore important to helping identify patients with VBDS early in the disease process. A lower threshold for liver transplantation assessment is recommended for those cases.